Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors

Suebsuwong, Chalada; Pinkas, Daniel; Ray, Soumya S.; Bufton, J.C.; Dai, Bing; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D.

doi:10.1016/j.bmcl.2018.01.044

Cited by 20 publications

(25 citation statements)

References 21 publications

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“…A-loop interactions remain a curiosity among kinase inhibitors but have been reported in some cases and the potential for target selectivity discussed [ 9 ]. Here, we demonstrate that stabilization of A-loop interactions may give rise to both exquisite selectivity, as well as a specific kinetic profile.…”

Section: Discussionmentioning

confidence: 99%

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A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

Pflug

Schimpl

Nissink

et al. 2020

Biochemical Journal

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The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.

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Section: Discussionmentioning

confidence: 99%

“…Binding to the back pocket allows for contacts between small molecule inhibitor and the kinase activation loop (A-loop). Such interactions have been described for several kinases, including c-Met, MEK1, RIPK1 and RIPK2 (reviewed by [ 9 ]), and can contribute to both binding potency and kinome selectivity.…”

Section: Introductionmentioning

confidence: 99%

A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

Pflug

Schimpl

Nissink

et al. 2020

Biochemical Journal

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“…This work is the first to demonstrate the efficacy and modulatory activity of a RIP2 targeting compound using a clinically relevant model of allergic asthma. Numerous inhibitors have both been discovered and developed for modulation of RIP2 activity (23,(35)(36)(37)(38)(39)(40)(41)(42)(43). The RIP2 inhibitor utilized in this study, GSK583, has been reported to be highly selective and exhibits strong potency even in vivo (23,39).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Miller

Shehat

Tigno-Aranjuez

2020

Preprint

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AbstractExposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely T helper cell type 2 (Th2) dominant and a number of innate immune receptors have been identified which recognize HDM to initiate a Th2 response. Nucleotide-binding Oligomerization Domain-containing Protein 2 (NOD2) is a cytosolic sensor of peptidoglycan which is important for Th2 polarization. NOD2 mediates its signaling through its downstream effector kinase, Receptor-interacting Serine/Threonine Protein Kinase 2 (RIP2). We have previously shown that RIP2 is important in promoting HDM-associated allergic airway inflammation and Th2 immunity. In particular, we demonstrated that the effects of RIP2 were important early in the HDM response, likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while skewing the immune response from Th2 towards Th1. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2 targeted therapies.

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“…The structural model of the RIPK2-MKK7 complex was generated from available structures in the RCSB Protein Data Bank (PDB) 48 . Briefly, the 3D structure of the RIPK2 kinase domain was used from an available structure (PDB code 6ES0) 49 , and that of the MKK7 kinase domain was generated by homology modelling 50 , using the structure of MEK1 (PDB code 1S9I) 51 as a template. Putative dimerization models of kinase domains were generated with Rosetta 52 and ZDOCK 53 .…”

Section: Interactome Analysis By Immunoprecipitation-mass Spectrometrmentioning

confidence: 99%

RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

Yan

Zhou

Chen

et al. 2020

Preprint

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Despite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway-a novel, noncanonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc-a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival. MainProstate cancer is the second most common cancer in men worldwide and causes about 360,000 deaths each year 1 . Mortality is predominantly caused by metastases that almost invariably become resistant to castration and other therapies 2 . Despite significant advances in prostate cancer treatment in the past decade 3 , the relative five-year survival rate of patients with metastatic disease remains about 30% 4 . Hence, there is an urgent need to identify novel actionable drug targets for combating metastatic progression to lethal disease.

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Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors

Abstract: Graphical abstract

Cited by 20 publications

References 21 publications

A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

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